Hyaluronic acid (HA) and compositions comprising HA are known for long time. HA has been combined with various other compounds and applied in a number of medical applications. In gel formulations, such applications include treatment of joint problems, and particularly for knee joint problems.
An approved medical treatment is e.g. Synvisc-One™ (hylan G-F 20) of Genzyme Corporation indicated for the treatment of pain in osteoarthritis (OA) of the knee in patients.
Various compositions containing HA with other components are known in the art. Chitosan is of particular interest for its combination of biocompatibility, biodegradability, bioadhesivity as well as for its wound healing-promoting and bacteriostatic properties. (Pangburn S H, Trescony P V, Heller J. Lysozyme degradation of partially deacetylated chitin, its films and hydrogels. Biomaterials; 1982; 3:105-108; Tomihata K, Ikada Y. In vitro and in vivo degradation of films of chitin and its deacetylated derivatives. Biomaterials 1997; 18:567-575; Lehr C M, Bouwstra J A, Schacht E H, Junginger H E. In vitro evaluation of mucoadhesive properties of chitosan and some other natural polymers. Int J Pharm 1992; 78:43-48; Ueno H, Mori T, Fujinaga T. Topical formulations and wound healing applications of chitosan. Adv Drug Deliv Rev 2001; 52:105-115; Liu N, Chen X G, Park H J, Liu C G, Liu C S, Meng X H, Yu L J. Effect of MW and concentration of chitosan on antibacterial activity of Escherichia coli. Carbohydr Polym 2006; 64:60-65.)
Combining HA and chitosan has been attempted in many ways. For example, U.S.2009/0238874 A1 describes Biomimetic compositions reinforced by a polyelectrolytic complex of hyaluronic acid and chitosan. HA and chitosan are assembled in dry form without any excipient addition. The compounds are arranged as polyionic complexes representing a network of insoluble fibers and thin membranes wherein a phase separation leads to segregated HA-rich and chitosan-rich domains. Such a distribution is however undesirable for many applications.
A publication of Denuziere, A. et al. (Biomaterials 19: 1275-1285, 1998), describes chitosan-chondroitin sulfate and chitosan-hyaluronate polyelectrolyte complexes.
U.S.2006/0166928 A1 having the title “hyaluronic acid derivative gel and method for preparing the same” describes derivatized HA covalently linked to chitosan via EDC/NHS amidation having a HA:chitosan ratio of 5 to 40. The compound shows thermogelling ability.
U.S. 2009/0238875 titled “Chitosan or hyaluronic-poly (ethylene oxide) and chitosan-hyaluronic acid-poly (ethylene oxide) based hydrogels and manufacturing method therefore” refers to chitosan-polyethyleneoxide (PEO), HA-PEO, chitosan-HA-PEO hydrogels obtained by chemical addition via acrylate chemistry for use in delivering proteins and peptides.
CN 10167600 is concerned with HA-chitosan biomembranes.
U.S. Pat. No. 7,524,514 relates to biomimetic compositions reinforced by a polyelectrolytic complex of HA and chitosan.
Hydrogels consist of three-dimensional networks of natural or synthetic polymers dispersed in water. Physical or chemical crosslinking ensure the insolubility and stability of the polymer gel. Hydrogels exhibit high absorbance for water and can contain as much as 99.9% water. It can be desired to have hydrogels which are clear and do not contain any aggregates. Hydrogels formed from HA and chitosan without a significant amount of aggregates have so far not been described and would be useful for a number of medical applications.
The above state of the art does neither disclose nor suggest the below described invention. In particular, the prior art does not disclose or suggest transparent aggregate-free gels.